Most, if not all, cancers have epigenetic changes, which are proposed to contribute to oncogenesis. However, it is difficult to evaluate the contribution of epigenetic changes in the setting of genome instability. SNF5 (INI1/SMARCB1/BAF47) is specifically mutated in aggressive human cancers and in a familial cancer predisposition syndrome. In the previous funding period we found that SNF5 loss does not affect DNA repair or chromosome stability but rapidly leads to aggressive cancers that lack genome instability and possess widespread epigenetic alterations. While it has been hypothesized that SNF5 loss leads to inactivation of the SWI/SNF complex, we have additional evidence that tumorigenesis is rather caused by aberrant activation of the residual complex. Indeed, SNF5-deficient cancers are abolished by concomitant loss of BRG1, the core ATPase of the SWI/SNF complex. This proposal will exploit unique reagents developed in the laboratory to test our hypothesis that cancer caused by SNF5 loss is driven by dysfunctional nucleosome position at specific promoters caused by neomorphic effects of a partially functional SWI/SNF complex and we will also identify the epigenetically regulated pathways that cooperate with SNF5 loss. Aim 1: What are the effects of Snf5 inactivation upon nucleosome positioning? Aim 2: What are the effects of Snf5 loss upon the targeting and composition of the Swi/Snf complex? Aim 3: What genes cooperate with Snf5 loss in oncogenic transformation? Significance: The Swi/Snf complex is mutated in a variety of human cancers. No studies have evaluated the role of SNF5 in nucleosome remodeling or targeting, fundamental activities of the SWI/SNF complex. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of an epigenetic regulator causes the rapid onset of aggressive, lethal cancers in the absence of genome instability and identify novel epigenetically based targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: SNF5 and other subunits of the SWI/SNF chromatin remodeling complex are specifically mutated in a variety of aggressive human cancers and in a familial cancer syndrome. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of this complex causes the rapid onset of aggressive, lethal cancers and identify novel targets for therapeutic intervention.